The amyloid-β oligomer Aβ∗56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation

Fatou Amar, Mathew A Sherman, Travis Rush, Megan Larson, Gabriel Boyle, Liu Chang, Jürgen Götz, Alain Buisson, Sylvain E Lesne

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Oligomeric forms of amyloid-forming proteins are believed to be the principal initiating bioactive species in many neurodegenerative disorders, including Alzheimer's disease (AD). Amyloid-β (Ab) oligomers are implicated in AD-associated phosphorylation and aggregation of the microtubule-associated protein tau. To investigate the specific molecular pathways activated by different assemblies, we isolated various forms of Aβ from Tg2576 mice, which are a model for AD. We found that Aβ∗56, a 56-kDa oligomer that is detected before patients develop overt signs of AD, induced specific changes in neuronal signaling. In primary cortical neurons, Aβ∗56 interacted with N-methyl-D-aspartate receptors (NMDARs), increased NMDAR-dependent Ca2+ influx, and consequently increased intracellular calcium concentrations and the activation of Ca2+-dependent calmodulin kinase IIa (CaMKIIa). In cultured neurons and in the brains of Tg2576 mice, activated CaMKIIa was associated with increased site-specific phosphorylation and missorting of tau, both of which are associated with AD pathology. In contrast, exposure of cultured primary cortical neurons to other oligomeric Aβ forms (dimers and trimers) did not trigger these effects. Our results indicate that distinct Aβ assemblies activate neuronal signaling pathways in a selective manner and that dissecting the molecular events caused by each oligomer may inform more effective therapeutic strategies. 2017

Original languageEnglish (US)
Article numberaal2021
JournalScience signaling
Volume10
Issue number478
DOIs
StatePublished - May 9 2017

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Phosphorylation
Oligomers
Amyloid
Alzheimer Disease
Agglomeration
Neurons
Calcium-Calmodulin-Dependent Protein Kinases
N-Methyl-D-Aspartate Receptors
Amyloidogenic Proteins
Microtubule-Associated Proteins
Pathology
Neurodegenerative Diseases
Dimers
Brain
Chemical activation
Calcium
Proteins

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The amyloid-β oligomer Aβ∗56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. / Amar, Fatou; Sherman, Mathew A; Rush, Travis; Larson, Megan; Boyle, Gabriel; Chang, Liu; Götz, Jürgen; Buisson, Alain; Lesne, Sylvain E.

In: Science signaling, Vol. 10, No. 478, aal2021, 09.05.2017.

Research output: Contribution to journalArticle

Amar, Fatou ; Sherman, Mathew A ; Rush, Travis ; Larson, Megan ; Boyle, Gabriel ; Chang, Liu ; Götz, Jürgen ; Buisson, Alain ; Lesne, Sylvain E. / The amyloid-β oligomer Aβ∗56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. In: Science signaling. 2017 ; Vol. 10, No. 478.
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